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Re-sensitizing ER-Alpha Mutant Breast Cancer Cells to Hormonal Therapy

Re-sensitizing ER-Alpha Mutant Breast Cancer Cells to Hormonal Therapy
使 ER-Alpha 突变乳腺癌细胞对激素疗法重新敏感
批准号:
9302315
负责人:
Rong Li
金额:
$16.58万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-07-01 至 2018-06-30

项目摘要

项目成果

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中文摘要
翻译
摘要 大多数乳腺癌病例为雌激素受体(ERα)阳性。虽然激素治疗 改善约一半ERα阳性乳腺癌患者的临床结局,无论是新发还是获得性 耐药性是一个重大的临床挑战。在几种基本机制中,热点点 已知ERα突变体由于其雌激素非依赖性转录, 活动因此,减轻这些ERα突变体的异常转录活性有望克服 ERα阳性乳腺癌的治疗耐药。作为ER家族的第二个成员, ERβ能够通过异源二聚化和/或竞争共同的 染色质结合位点。ERβ的这种ERα干扰功能可用于克服 治疗抗性ERα突变体。然而,这种方法的临床可行性还远远没有被探索,因为 关于ERβ的ERα干扰活性是如何被动员的,我们知之甚少。 我们的前期工作发现了ERβ中一个重要的磷酸酪氨酸开关。具体地说, 我们发现未磷酸化的ERβ在异源二聚化和功能干扰中特别有效 ERα。因此,我们假设ERα阳性乳腺癌中未磷酸化的ERβ可能有助于 克服ERα突变体介导的治疗抗性。我们进一步设想, 微调ERβ的磷酸酪氨酸状态可能在临床上有用, 活动我们将通过两个具体目标来检验这个新的假设。首先,我们将使用体外和病人- 衍生的异种移植物模型,以确定ERβ磷酸化状态对ERα介导的治疗性 阻力其次,我们将使用分子和药理学工具来阐明 ERβ磷酸化状态调节ERα/β串扰。 通过聚集一种特定形式的ERβ来克服治疗耐药性的概念代表了一种新的治疗方法。 新概念。此外,由于磷酸酪氨酸开关的上游激酶的抑制剂是 临床上可获得的和ERβ特异性激动剂在人体中耐受良好,我们的工作提供了多个 用于精细调节ERβ活性和治疗ERα阳性乳腺癌的即将发生的可转化性的药物靶点 癌我们提出的研究承诺在理解如何 克服对激素治疗的治疗抗性,这是乳腺癌治疗中的紧迫临床挑战。
英文摘要
ABSTRACT The majority of breast cancer cases are estrogen receptor (ERα)-positive. While hormonal therapy improves clinical outcomes for about half of patients with ERα-positive breast cancer, de novo or acquired resistance represents a significant clinical challenge. Among several underlying mechanisms, hot-spot point mutants of ERα are known to confer therapeutic resistance due to their estrogen-independent transcriptional activity. Thus, mitigating aberrant transcription activity of these ERα mutants holds promise for overcoming therapeutic resistance in treatment of ERα-positive breast cancer. As the second member of the ER family, ERβ is capable of interfering with ERα activity through heterodimerization and/or competing for common chromatin binding sites. This ERα-interfering function of ERβ could be utilized to overcome the activity of therapeutically resistant ERα mutants. However, clinical feasibility of this approach is vastly under-explored, as little is known about how ERα-interfering activity of ERβ is mobilized. Our preliminary work discovered a functionally important phosphotyrosine switch in ERβ. Specifically, we found that unphosphorylated ERβ is particularly potent in heterodimerization and functional interference with ERα. We therefore hypothesize that unphosphorylated ERβ in ERα-positive breast cancer can help overcome ERα mutant-mediated therapeutic resistance. We further envision that pharmacological agents that fine-tune the phosphotyrosine status of ERβ could be clinically useful in stimulating its ERα-interfering activity. We will test this novel hypothesis through two Specific Aims. First, we will use in vitro and patient- derived xenograft models to determine the impact of ERβ phosphorylation status on ERα-mediated therapeutic resistance. Second, we will use molecular and pharmacological tools to elucidate the mechanism by which ERβ phosphorylation status regulates the ERα/β crosstalk. The concept of overcoming therapeutic resistance by rallying a particular form of ERβ represents a novel concept. Furthermore, because the inhibitor of the upstream kinase for the phosphotyrosine switch is clinically available and ERβ-specific agonists are well tolerated in humans, our work provides multiple druggable targets for fine-tuning ERβ activities and imminent translatability for treating ERα-positive breast cancer. Our proposed study promises both conceptual and translational advances in understanding of how to overcome therapeutic resistance to hormonal therapy, a pressing clinical challenge in breast cancer treatment.
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Regulation of anti-tumor immunity by HDAC11
  • 批准号:
    10436938
  • 项目类别:
  • 资助金额:
    $56.97万
  • 财政年份:
    2020
  • 负责人:
    Rong Li
  • 依托单位:
Boosting Antitumor Immunity by Blocking Both Tumor and Adipose DDR1
  • 批准号:
    9980667
  • 项目类别:
  • 资助金额:
    $47.69万
  • 财政年份:
    2020
  • 负责人:
    Rong Li
  • 依托单位:
Regulation of anti-tumor immunity by HDAC11
  • 批准号:
    10524141
  • 项目类别:
  • 资助金额:
    $8.44万
  • 财政年份:
    2020
  • 负责人:
    Rong Li
  • 依托单位:
Regulation of anti-tumor immunity by HDAC11
  • 批准号:
    10640210
  • 项目类别:
  • 资助金额:
    $56.14万
  • 财政年份:
    2020
  • 负责人:
    Rong Li
  • 依托单位:
国内基金
海外基金
Agonist-GPR119-Gs复合物的结构生物学研究
  • 批准号:
    32000851
  • 项目类别:
    青年科学基金项目
  • 资助金额:
    24.0万元
  • 批准年份:
    2020
  • 负责人:
    乔安娜
  • 依托单位: